Process for the preparation of piperidinylaminomethyl trifluoromethyl cyclic ether compounds

ABSTRACT

The present invention relates to a novel process for the preparation of a diastereomeric mixture of piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib:  
                 
 
     and pharmaceutically acceptable salts thereof, wherein R 1  is C 1 -C 6  alkyl; R 2  is C 1 -C 6  alkyl, halo C 1 -C 6  alkyl or phenyl or substituted phenyl; R 3  is hydrogen or halo; m is zero, one or two, and wherein said mixture is highly enriched in the compound of formula Ia, and to novel processes for the preparation and purification of intermediate compounds useful in the preparation of compounds of formulae Ia and Ib.

BACKGROUND OF INVENTION

[0001] The present invention relates to a novel process for thepreparation of a diastereomeric mixture of piperidinylaminomethyltrifluoromethyl cyclic ether compounds of formulae Ia and Ib:

[0002] and pharmaceutically acceptable salts thereof, wherein R¹ isC₁-C₆ alkyl;R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenyl or substitutedphenyl;R³ is hydrogen or halo; m is zero, one or two.

[0003] Further, the present invention also relates to a process for thepreparation of a diastereomeric mixture of compounds of formulae Ia andIb, and pharmaceutically acceptable salts thereof, highly enriched inthe compound of formula Ia. The process of the present invention permitsvia selective crystallization the isolation of diastereomeric mixturesof compounds of formula Ia and Ib wherein the ratio of compounds offormula Ia to Ib are in excess of 90:10.

[0004] In addition, the present invention relates to novel processes forthe preparation of a compound of formula II:

[0005] an intermediate compound useful in the preparation of compoundsof formulae Ia and Ib. In addition, the present invention is alsodirected to other novel intermediates useful in the process forpreparing the mixture of compounds of formulae Ia and Ib. The presentinvention is also directed to a novel process for the purification ofcertain intermediates for use in the methods of the invention.

[0006] The compounds of formula Ia and Ib, particularly compounds offormula Ia, and pharmaceutically acceptable salts thereof, are useful asantagonists of substance P, a naturally-occurring undecapeptidebelonging to the tachykinin family of peptides that is widely involvedin the pathophysiology of numerous diseases, including central nervoussystem disorders such as depression, anxiety and schizophrenia, inrespiratory and inflammatory diseases such as asthma and rheumatoidarthritis, in gastrointestinal disorders and diseases of the GI tractsuch as ulcerative colitis and Crohn's disease, and in the transmissionof pain, including migraine.

[0007] The diastereomeric mixture of compounds of formulae Ia and Ib anda process of making that diastereomeric mixture are described inInternational Patent Publication No. WO 99/25714, published May 27,1999. That reference refers to methods of preparing the diastereomericmixture using methods other than those of the present invention, and ishereby incorporated by reference in its entirety. The present inventionprovides a more practical, more direct and higher yielding process forpreparing a mixture of diastereomers of compounds of formulae Ia and Ib,highly enriched in the compound of formula Ia, via novel syntheticpathways.

SUMMARY OF INVENTION

[0008] The present invention relates to a process for the preparation ofa mixture of compounds of formulae Ia and Ib:

[0009] highly enriched in the presence of the compound of formula Ia,and pharmaceutically acceptable salts thereof, wherein

[0010] R¹ is C₁-C₆ alkyl;

[0011] R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenyl or substitutedphenyl;

[0012] R³ is hydrogen or halo;

[0013] m is zero, one or two;

[0014] comprising the steps of (a1) reacting a mixture of compounds offormulae Ia and Ib:

[0015] with an acid of formula HX, wherein HX is selected from the groupconsisting of (S)-(+)-mandelic acid, D-(−)-tartaric acid,di-p-toluoyl-D-tartaric acid,((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, aceticacid and hydrobromic acid, to form a mixture of diastereomeric compoundsof formulae Va and Vb, respectively, enriched in the presence of acompound of formula Va:

[0016] (b1) permitting the HX salt of the diastereomeric product mixtureof step (a1) to crystallize out of a solution thereof in an appropriatesolvent; and

[0017] (c1) treating the resulting mixture of compounds obtained fromstep (c1) with a base.

[0018] A most preferred embodiment of the invention is where the acid HXof step (a1) is (S)-(+)-mandelic acid. A more preferred embodiment ofthe invention is where the appropriate solvent of step (a1) is selectedfrom the group consisting of methanol, ethanol, isopropanol,tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl-tert-butylether, diisopropyl ether, toluene, acetonitrile, acetone, water and amixture of any of the foregoing solvents. A most preferred embodiment iswhere the appropriate solvent of step (a1) is ethanol. A more preferredembodiment of the invention is where the base of step (c1) is selectedfrom the group consisting of sodium hydroxide, potassium hydroxide,sodium carbonate, sodium bicarbonate, potassium carbonate and potassiumbicarbonate.

[0019] The present invention also relates to the preparation of thepharmaceutically acceptable salts of the mixture of compounds of formulaIa and Ib, highly enriched in the compound of formula Ia, whichcomprises treating the mixture of compounds Ia and Ib that is enrichedin one of the diastereomeric compounds of formula Ia with a proton acid,H⁺Y⁻, wherein the anion, Y⁻, is selected from the group consisting ofhydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, pandpamoate (i.e., 1,1′to form a mixture of compounds VIa and VIb, highlyenriched in the diastereomeric compound acid addition salt of formulaVIa:

[0020] wherein n is determined by the intrinsic characteristics of theform of the compounds Ia and Ib when completed with the particular acidHY, and n is an integer from one to two. The process of the inventionalso relates to the preparation of the hydrates of the compounds offormula VIa and VIb, in which between zero and three molecules of watermay be associated with each molecule of the compounds of formula VIa andVIb, said hydrates being formed in the step in which compounds offormula Ia and Ib are treated with a proton acid.

[0021] A more preferred embodiment of the invention is where the protonacid used is hydrochloric acid, and n is 2. A preferred embodiment ofthe invention is where the ratio of compound VIa and VIb obtained is90:10 or greater. A more preferred embodiment of the invention is wherethe ratio of compound VIa and VIb obtained is 98:2 or greater.

[0022] The present invention also relates to a process for thepreparation of compounds of formulae Ia and Ib, highly enriched in thepresence of a compound of formula Ia, further comprising the step ofreacting a compound of formula III:

[0023] with a compound of formula IV:

[0024] in the presence of a reducing agent to obtain a mixture ofcompounds of formula Ia and Ib.

[0025] A preferred embodiment of the invention is where the reducingagent is selected from the group consisting of sodiumtriacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. Amore preferred embodiment of the invention is where the reducing agentis sodium triacetoxyborohydride.

[0026] The present invention also relates to the process for thepreparation of compounds of formulae Ia and Ib, highly enriched in thepresence of a compound of formula Ia, further comprising the step offormylating a compound of formula II:

[0027] wherein R¹, R² and R³ are as defined above; m is 0, 1 or 2 withhexamethylenetetramine, in the presence of an acid to form a compound offormula III. A preferred embodiment of the invention is where the acidin the formulation reaction is trifluoroacetic acid, glyceroboric acid,acetic acid or hydrochloric acid. The most preferred acid istrifluoroacetic acid. The present invention also relates to the processfor the preparation of compounds of formulae Ia and Ib, highly enrichedin the presence of a compound of formula Ia, wherein the compound offormula II:

[0028] wherein R¹, R² and R³ are as defined above; m is 0, 1 or 2; isprepared by a process comprising the steps of (a2) reacting a compoundof formula VII:

[0029] with a compound of formula CF₃SiR⁴ ₃, wherein R⁴ is (C₁-C₆)alkylor phenyl, in the presence of a fluoride source to form a compound offormula VIII:

[0030] (b2) removing the silyl protecting group from the product of step(a2) via treatment with a base or a fluoride source to form a compoundof formula IX:

[0031] (c2) hydrolyzing the ester group of the product of step (b2) inthe presence of a base to form a compound of formula X:

[0032] and (d2) performing a ring cyclization reaction on the product ofstep (c2) in the presence of a base and an activating agent selectedfrom the group consisting of methanesulfonyl chloride, methanesulfonicanhydride, p-toluenesulfonyl chloride, p anhydride and triflicanhydride.

[0033] A more preferred embodiment of the present invention is where thefluoride source in step (a2) is selected from the group consisting ofcesium fluoride, potassium fluoride and an alkylammonium fluoride. Themost preferred alkylammonium fluoride is tetrabutylammonium fluoride. Amost preferred embodiment of the invention is where the fluoride sourcein step (a2) is cesium fluoride. Preferred solvents for step (a2) aredimethylformamide, dimethylacetamide, toluene, dichloromethane,dichloroethane and tetrahydrofuran. The most preferred solvent for step(a2) is dimethylformamide.

[0034] In step (b2), the preferred bases are sodium hydroxide orpotassium hydroxide, and the preferred fluoride sources aretetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid-pyridinecomplex and hydrofluoric acid. The most preferred fluoride source istetrabutylammonium fluoride. Preferred solvents for step (b2) aretetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butylether, dichloromethane and toluene. The most preferred solvent for step(b2) is tetrahydrofuran.

[0035] The preferred bases in step (c2) are sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate andpotassium bicarbonate. The preferred base in step (c2) is sodiumhydroxide. Preferred solvents for step (c2) are water, tetrahydrofuran,methanol, ethanol, isopropanol, 1,4-dioxane and a combination of any ofthese solvents. The most preferred solvent for step (c2) is a mixture ofwater and tetrahydrofuran.

[0036] In step (d2), the most preferred activating agent ismethanesulfonyl chloride. Preferred bases for step (d2) aretriethylamine, diisopropylethylamine, 2,6-lutidine, pyridine, sodiumhydroxide, potassium hydroxide, cesium carbonate and potassiumcarbonate. The most preferred base for step (d2) is triethylamine.Preferred solvents for step (d2) are dichloromethane, tetrahydrofuran,toluene, diisopropyl ether and methyl-tert-butyl ether. The mostpreferred solvent for step (d2) is dichloromethane.

[0037] The present invention also relates to the process for thepreparation of compounds of formulae Ia and Ib, highly enriched in thepresence of a compound of formula Ia, wherein the compound of formulaII:

[0038] wherein R¹, R² and R³ are as defined above; m is 0, 1 or 2;comprising the steps of (a3) reacting a compound of formula XI:

[0039] with an alcohol of formula R¹OH in the presence of an acid,wherein R¹ is as defined above, to form a compound of formula XII:

[0040] (b3) reacting the product of step (a3) with compound of formulaCF₃SiR⁴ ₃, wherein R⁴ is (C₁-C₆)alkyl or phenyl, to form a compound offormula XII:

[0041] (c3) reacting the product of step (b3) with a fluoride source toobtain a lactone compound of formula XIV:

[0042] (d3) reacting the lactone product of step (c3) with a reducingagent optionally in the presence of a Lewis acid to obtain a compound offormula XV:

[0043] and (e3) reacting the product of step (d3) with a reducing agentoptionally in the presence of a Lewis acid to obtain a compound offormula II.

[0044] Another preferred embodiment of the invention is where the acidof step (a3) is chosen from the group consisting of sulfuric acid,hydrochloric acid, hydrobromic acid, trifluoroacetic acid andmethanesulfonic acid. The most preferred acid for step (a3) is sulfuricacid.

[0045] In step (b3), preferred fluoride sources are cesium fluoride,potassium fluoride and an alkylammonium fluoride, such astetrabutylammonium fluoride. The most preferred fluoride source iscesium fluoride. Preferred solvents for step (b3) are dimethylformamide,dimethylacetamide, dichloromethane and tetrahydrofuran. The mostpreferred solvent for step (b3) is dimethylformamide.

[0046] Preferred fluoride sources for step (c3) are tetrabutylammoniumfluoride, cesium fluoride, hydrofluoric acid-pyridine complex andhydrofluoric acid. The most preferred fluoride source for step (c3) istetrabutylammonium fluoride. Preferred solvents for step (c3) aretetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butylether, dichloromethane and toluene. The most preferred solvent for step(c3) is tetrahydrofuran.

[0047] Preferred reducing agents for step (d3) are sodium borohydride,borane tetrahydrofuran complex, borane dimethylsulfide complex,diborane, lithium borohydride, calcium borohydride, lithium aluminumhydride, diisobutylaluminum hydride, L-selectride and K-selectride. Themost preferred reducing agent is sodium borohydride. The preferred Lewisacid for step (d3) is boron trifluoride diethyl ether complex. Preferredsolvents for step (d3) are tetrahydrofuran, diisopropyl ether,methyl-tert-butyl ether and dimethoxyethane. The most preferred solventfor step (d3) is tetrahydrofuran.

[0048] The preferred reducing agents for step (e3) are triethylsilane ortriphenylsilane, in the presence of a Lewis acid such as borontrifluoride etherate or trifluoroacetic acid, preferably trifluoroaceticacid. Preferred solvents for step (e3) are dichloromethane,dichloroethane and chloroform. The most preferred solvent for step (e3)is dichloromethane.

[0049] Another preferred embodiment is where in step (e3) a compound offormula XIV is treated with a catalyst such as platinum, platinum oxide,or palladium hydroxide, preferably platinum, in a solvent such asmethanol, ethanol, or isopropanol, preferably ethanol, under anatmosphere of hydrogen, optionally under pressure greater thanatmospheric pressure.

[0050] The present invention also relates to the process for thepreparation of compounds of formulae Ia and Ib, highly enriched in thepresence of a compound of formula Ia, wherein the compound of formulaIII:

[0051] is purified by a method comprising the steps of (a4) forming ahydrazone via the reaction of a compound of formula III with a hydrazoneof formula XVI:

[0052] in the presence of an acid to afford a compound of formula XVII:

[0053] and (b4) hydrolyzing the product of step (a4) via treatment witha reagent selected from the group consisting of copper(II)chloride,copper(II)iodide, copper(II)acetate, copper sulfate, sulfuric acid,acetic acid and hydrochloric acid.

[0054] Preferred acids for step (a4) include acetic acid, sulfuric acid,hydrochloric acid, methanesulfonic acid and p-toluenesulfonic acid. Themost preferred acid for step (a4) is acetic acid. Preferred solvents forstep (a4) are methanol, ethanol, isopropanol, tetrahydrofuran, water anda mixture of any of the foregoing solvents. The most preferred solventfor step (a4) is a mixture of methanol and water.

[0055] The more preferred reagent for step (b4) is copper(II)chloride.Preferred solvents for step (b4) are tert-butyl alcohol, methanol,ethanol, isopropanol, tetrahydrofuran, water and a mixture of any of theforgoing solvents. The most preferred solvent for step (b4) is a mixtureof tert-butyl alcohol and water.

[0056] In addition, methods for the preparation of pharmaceuticalcompositions of mixtures of the compounds of formula Ia or Ib orpharmaceutically acceptable salts thereof are encompassed by the presentinvention. A method for the preparation of such a pharmaceuticalcomposition comprises the addition of a mixture of compounds of formulaIa and Ib or pharmaceutically acceptable salts thereof to apharmaceutically acceptable carrier or diluent.

[0057] The present invention is also directed to the novel intermediatesused in the methods of the invention, including but not limited to thosecompounds of formula VII, IX, XII, XIV, XV and XVII and salts thereof.

[0058] The term alkyl, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0059] The term substituted phenyl, as used herein, unless otherwiseindicated, means phenyl substituted by one or more, preferably one ortwo substituent(s) such as halogen, hydroxy, (C₁-C)alkyl or(C₁-C)alkoxy.

[0060] The term halo or halogen, as used herein, unless otherwiseindicated, means fluorine, chlorine, bromine or iodine.

[0061] The term suitable solvent or appropriate solvent, as used herein,unless otherwise indicated, means a medium which serves to dissolveparticular indicated substance(s), compound(s) or reagent(s) to form auniformly dispersed mixture of that substance or compound at themolecular or ionic level.

[0062] The term proton acid used to prepare acid addition salts of thecompounds of the process of this invention are those which form nonacidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, pand pamoate (i.e., 1,1′salts.

[0063] The term enriched, as used herein, unless otherwise indicated,means to predominate in a ratio of greater than 1:1 of one particularcompound or isomer over another or other components in a mixture. Theterm highly enriched, as used herein, unless otherwise indicated, meansto predominate in a ratio of at least 90:10 of one particular compoundor isomer over another or other component in a mixture. Unless otherwiseindicated, this invention relates to all optical isomers, tautomers andstereoisomers of the any of compounds described herein.

[0064] The term pharmaceutically acceptable salt, as used herein, unlessotherwise indicated, refers to an acid addition salt of a proton acid,as defined herein, or a hydrate of an acid addition salt.

DETAILED DESCRIPTION

[0065] A diastereomeric mixture of piperidinylaminomethyltrifluoromethyl cyclic ether compounds of formulae Ia and Ib, highlyenriched in a compound of formula Ia, may be prepared in accordance withthe novel method shown in reaction scheme 1 below.

[0066] Novel methods for the preparation of a critical intermediate inthe preparation of piperidinylaminomethyl trifluoromethyl cyclic ethercompounds, a compound of formula II, may be carried out in accordancewith schemes 2 and 3, below. A novel means for purifying a keyintermediate in the process of scheme 1 is shown in scheme 4. Unlessotherwise indicated, the variables R¹, R², R³, R⁴, m and n are asdescribed above.

[0067] Step 1 of scheme 1 is a formulation. A compound of formula II istreated with hexamethylenetetramine, in the presence of an acid such astrifluoroacetic acid, glyceroboric acid, acetic acid or hydrochloricacid, preferably trifluoroacetic acid, optionally in a solvent such asdichloromethane, dichloroethane, heptane, or nitromethane, preferablywithout a solvent at a temperature between 0 and 100° C., preferably at70° C., for a period of time between 10 minutes and 24 hours, preferably3 hours, followed by addition of water, to afford a compound of formulaIII. At this point, the compound of formula III may be purifiedaccording to the method of the invention as set forth below at scheme 4prior to proceeding with step 2.

[0068] Step 2 of scheme 1 is a reductive coupling. An aldehyde offormula III is treated with an amine of formula IV, or a salt thereof,in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride,preferably sodium triacetoxyborohydride, in a solvent, such asdichloromethane, dichloroethane, tetrahydrofuran, toluene, acetic acid,diisopropyl ether, or methyl-tert-butyl ether, preferablydichloromethane, at a temperature between −20 and 60° C., preferably 0°C., for a period of time between 30 minutes and 24 hours, preferably 3hours, to afford a mixture of compounds of formulae Ia and Ib.

[0069] Step 3 of scheme 1 is a salt formation. The mixture of compoundsIa and Ib is treated with an acid of formula HX, such as(S)-(+)-mandelic acid, D-(−)-tartaric acid, Di-p-toluoyl-D-tartaricacid, ((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid,acetic acid, hydrobromic acid, preferably (S)-(+)-mandelic acid, in asolvent, such as methanol, ethanol, isopropanol, tetrahydrofuran, ethylacetate, isopropyl acetate, methyl-tert-butyl ether, diisopropyl ether,toluene, acetonitrile, acetone, water, or a mixture of the foregoingsolvents, preferably ethanol, at a temperature between −20 and 70° C.,preferably room temperature, for a period of time between 30 minutes and48 hours, preferably 18 hours, to afford a mixture of compounds offormula Va and Vb which is enriched in compound of formula Vb. Step 3permits the isolation of mixtures of compounds of formula Va and Vbwherein the ratio of compounds of formula Va to Vb is greater than70:30, and generally 80:20 or greater.

[0070] Step 4 of scheme 1 is the formation of an acid addition salt. Themixture of compounds of formula Va and Vb highly enriched in compound Vais treated with a base such as sodium hydroxide, potassium hydroxide,sodium carbonate, sodium bicarbonate, potassium carbonate or potassiumbicarbonate, in water in the presence of a cosolvent such as toluene,diisopropyl ether, methyl-tert-butyl ether, ethyl acetate, ordichloromethane, preferably diisopropyl ether, at a temperature between0 and 40° C., preferably room temperature, for a period of time between10 minutes and 48 hours, preferably 18 hours, to afford a mixture ofcompounds of formula Ia and Ib which is enriched in compound of formulaIa. The ratio of compound Ia to Ib, obtained from this part of step 4 is70:30 or greater, but in general 80:20 or greater. This mixture istreated with a proton acid, HY, as defined above, preferablyhydrochloric acid, in a solvent, such as methanol, ethanol, isopropanol,tetrahydrofuran, diisopropyl ether, water or a mixture of the foregoingsolvents, preferably a mixture of methanol and water, at a temperaturebetween 0 and 60° C., preferably room temperature, for a period of timebetween 1 hour and 48 hours, preferably 18 hours, to afford a mixture ofcompounds of formula VIa and VIb which is highly enriched in compound offormula VIa, and wherein n is as defined above. Step 4 permits theisolation of mixtures of compounds of formula VIa and VIb wherein theratio of compounds of formula VIa to VIb are greater than 90:10, and mayapproach 98:2 or better. Step 4 may be repeated to obtain higher ratiosif needed.

[0071] Step 1 of scheme 2 is an acylation of an arene which proceedswith protection of an alcohol in a way similar to a known procedure(Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49,1574-1583). An arene of formula XVIII is treated with an acylating agentof formula R²(C═O)—X″, wherein R² is as defined above and X″ is halo,R²(C═O)—O—, or other suitable group in an acylating agent recognized bythose of skill in the art, in the presence of an acid such as aluminumtribromide, aluminum trichloride, tin tetrachloride, titaniumtetrachloride, or polyphosphoric acid, preferably aluminum tribromide,in a solvent such as dichloromethane, dichloroethane, nitromethane,nitrobenzene, carbon disulfide, or chlorobenzene, preferablydichloromethane, at a temperature between −20° C. and 125° C.,preferably between 0 and 20° C., for a period between 10 minutes to 10hours, preferably about 1 hour, to afford a compound of formula VII.

[0072] Step 2 of scheme 2 is the addition of a trifluoromethyl group toa ketone using a modification of a known method (Prakash, G. K. S.;Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395).Ketone of formula VII is treated with a compound of formula CF₃SiR⁴ ₃,wherein R⁴ is defined above, in the presence of a fluoride source suchas cesium fluoride, potassium fluoride, or an alkylammonium fluoridesuch as tetrabutylammonium fluoride, preferably cesium fluoride, in thepresence of a solvent such as dimethylformamide, dimethylacetamide,toluene, dichloromethane, dichloroethane, or tetrahydrofuran, preferablydimethylformamide, at a temperature between −78° C. and 50° C.preferably at room temperature, for a period of time between 10 minutesand 18 hours, preferably 45 minutes, to afford a compound of formulaVIII.

[0073] Step 3 of scheme 2 is the deprotection of an alcohol. A compoundof formula VIII is treated with a reagent such as sodium hydroxide,potassium hydroxide, or a fluoride source such at tetrabutylammoniumfluoride, cesium fluoride, hydrofluoric acid-pyridine complex, orhydrofluoric acid, preferably tetrabutylammonium fluoride, in a solventsuch as tetrahydrofuran, diisopropyl ether, acetonitrile,methyl-tert-butyl ether, dichloromethane, or toluene, preferablytetrahydrofuran, at a temperature between −40 and 60° C., preferablyroom temperature, for a period of time between 5 minutes and 5 hours,preferably one hour, to afford a compound of formula IX.

[0074] Step 4 of scheme 2 is the hydrolysis of an ester. A compound offormula IX is treated with a reagent such as sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, preferably sodium hydroxide, in a solvent such aswater, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane, ora combination of the above solvents, preferably a mixture of water andtetrahydrofuran, at a temperature between 0 and 75° C., preferably roomtemperature, for a period of time between 1 and 48 hours, preferably 12hours, to afford a compound a formula X.

[0075] Step 5 of scheme 2 is a cyclization. A compound of formula X istreated with an activating agent such as methanesulfonyl chloride,methanesulfonic anhydride, p toluenesulfonyl chloride, p-toluenesulfonicanhydride, or triflic anhydride, preferably methanesulfonyl chloride,and a base such as triethylamine, diisopropylethylamine, 2,6-lutidine,pyridine, sodium hydroxide, potassium hydroxide, cesium carbonate, orpotassium carbonate, preferably triethylamine, in a solvent such asdichloromethane, tetrahydrofuran, toluene, diisopropyl ether, ormethyl-tert-butyl ether, preferably dichloromethane, at a temperaturebetween −40 and 75° C., preferably between 0° C. and room temperature,for a period of time between one and 48 hours, preferably 12 hours, toafford a compound of formula II.

[0076] Step 1 of scheme 3 an acylation of an arene. An arene of formulaXIX is treated with an acylating agent of formula R²(C═O)—X″, wherein R²is as defined above and X″ is halo, R²(C═O)—O— or other suitable groupin an acylating agent recognized by those of skill in the art, in thepresence of an acid, such as aluminum tribromide, aluminum trichloride,tin tetrachloride, titanium tetrachloride, or polyphosphoric acid,preferably aluminum tribromide, in a solvent such as dichloromethane,dichloroethane, nitromethane, nitrobenzene, carbon disulfide orchlorobenzene, preferably dichloromethane, at a temperature between −20°C. and 125° C., preferably between 0 and 20° C., for a period between 10minutes to 10 hours, preferably about 1 hour, to afford a compound offormula XI.

[0077] Step 2 of scheme 3 is an esterification. A carboxylic acid offormula XI is treated with an alcohol of formula R¹OH, wherein R¹ isdefined above, in the presence of an acid such as sulfuric acid,hydrochloric acid, hydrobromic acid, trifluoroacetic acid ormethanesulfonic acid, preferably sulfuric acid, at a temperature between0 and 100° C., preferably at room temperature, for a period between 10minutes to 48 hours, preferably 16 hours, to afford a compound offormula XII.

[0078] Step 3 of scheme 3 is the addition of a trifluoromethyl group toa ketone using a modification of a known method (Prakash, G. K. S.;Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395).Ketone of formula XII is treated with a compound of formula CF₃SiR⁴ ₃,wherein R⁴ is defined above, in the presence of a fluoride source suchas cesium fluoride, potassium fluoride or an alkylammonium fluoride,such as tetrabutylammonium fluoride; preferably cesium fluoride, in thepresence of a solvent such as dimethylformamide, dimethylacetamide,dichloromethane or tetrahydrofuran, preferably dimethylformamide, at atemperature between −78° C. and 50° C. preferably at 0° C., for a periodof time between 10 minutes and 18 hours, preferably 7 hours, to afford acompound of formula XII.

[0079] Step 4 of scheme 3 is a lactonization. A compound of formula XIIIis treated with a fluoride source such at tetrabutylammonium fluoride,cesium fluoride, hydrofluoric acid-pyridine complex or hydrofluoricacid, preferably tetrabutylammonium fluoride, in a solvent such astetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butylether, dichloromethane or toluene, preferably tetrahydrofuran, at atemperature between −40 and 60° C., preferably room temperature, for aperiod of time between 5 minutes and 5 hours, preferably one hour, toafford a compound of formula XIV.

[0080] Step 5 of scheme 3 is the reduction of a lactone. A compound offormula XIV is treated with a reducing agent such as sodium borohydride,borane tetrahydrofuran complex, borane dimethylsulfide complex,diborane, lithium borohydride, calcium borohydride, lithium aluminumhydride, diisobutylaluminum hydride, L-selectride or K-selectride,optionally in the presence of a Lewis acid, such as boron trifluoridediethyl ether complex; preferably sodium borohydride in the presence ofboron trifluoride diethyl ether complex, in a solvent, such astetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether ordimethoxyethane, preferably tetrahydrofuran, at a temperature between−78 and 60° C., preferably between 0° C. and room temperature, for aperiod of time between 30 minutes and 48 hours, preferably 16 hours, toafford a compound of formula XV.

[0081] Step 6 of scheme 3 is a reduction. A compound of formula XV istreated with a reducing agent such as triethylsilane or triphenylsilane,in the presence of a Lewis acid such as boron trifluoride etherate ortrifluoroacetic acid preferably trifluoroacetic acid, in a solvent suchas dichloromethane, dichloroethane, or chloroform, preferablydichloromethane at a temperature between −78 and 60° C., preferably roomtemperature, for a period of time between 5 minutes and S hours,preferably 2 hours, to afford a compound of formula II. Alternatively, acompound of formula XV is treated with a reducing agent that is acatalyst, such as platinum, platinum oxide, or palladium hydroxide,preferably platinum, in a solvent such as methanol, ethanol, orisopropanol, preferably ethanol, under an atmosphere of hydrogen,optionally under pressure, at a temperature between room temperature and100° C., preferably room temperature, for a period of time between 1 and48 hours, preferably 5 hours, to afford a compound of formula II.

[0082] Alternatively, compound III can be purified by derivatization.Step 1 of scheme 4 is the formation of a hydrazone. A compound offormula III is treated with a hydrazone of formula XVI with an acid suchas acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acidor p-toluenesulfonic acid, preferably acetic acid, in a solvent such asmethanol, ethanol, isopropanol, tetrahydrofuran, water or a mixture ofany of the foregoing solvents, preferably a mixture of methanol andwater, at a temperature between 0 and 110° C., preferably at reflux, fora period of time between 30 minutes and 10 hours, preferably 90 minutes,to afford a compound of formula XVII.

[0083] Step 2 of scheme 4 is the hydrolysis of a hydrazone. A compoundof formula XVII is treated a reagent such as copper(II)chloride,copper(II)iodide, copper(II)acetate, copper sulfate, sulfuric acid,acetic acid or hydrochloric acid, preferably copper(II)chloride, in asolvent such as tert-butyl alcohol, methanol, ethanol, isopropanol,tetrahydrofuran, water or a mixture of any of the foregoing solvents,preferably a mixture of tert-butyl alcohol and water, at a temperaturebetween 0 and 110° C., preferably at 70° C., for a period of timebetween 30 minutes and 10 hours, preferably 2.5 hours, to afford acompound of formula III.

[0084] The preparation of other compounds of the present invention notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0085] In each of the reactions discussed or illustrated in Schemes 1-4above, pressure is not critical, unless otherwise indicated. Pressuresfrom about 0.9 atmospheres to about 2 atmospheres are generallyacceptable and ambient pressure, i.e., about 1 atmosphere, is preferredas a matter of convenience.

[0086] Intermediate compounds of invention referred to above may containchiral centers, and therefore may exist in different enantiomeric anddiastereomeric forms; this invention is directed to all such optical andstereoisomers of said intermediate compounds, as well as mixturesthereof.

[0087] This invention is also directed to isotopically-labeled compoundsidentical to those recited in formulae Ia or Ib, or pharmaceuticallyacceptable salts thereof, but for the fact that one or more atoms arereplaced therein by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of thisinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.

[0088] Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds, or of saidprodrugs, which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful, for example, in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Furthermore, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances.

[0089] Isotopically labeled compounds of formulae Ia and Ib of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures set forth herein, by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

[0090] The activity, methods for testing activities, dosages, dosageforms, methods of administration and background information concerningthe compounds of formula Ia and Ib are set forth in International PatentPublication No. WO 99/25714, published May 27, 1999. Thepiperidinylaminomethyl trifluoromethyl cyclic ether compounds preparedby the methods of the present invention exhibit significant substance Preceptor-binding activity and are of value in the treatment of a widevariety of clinical conditions which are characterized by the presenceof an excess of said substance P activity. Such conditions includecardiovascular diseases, allergic disorders, angiogenesis,gastrointestinal disorders, central nervous system disorders,inflammatory diseases, emesis, urinary incontinence, pain, migraine,sunburn, and diseases, disorders and conditions caused by Helicobacterpylori, in a mammal, especially humans. For treatment of emesis, thesecompounds may preferably be used in combination with a 5-HT₃ antagonist.

[0091] The active piperidinylaminomethyl trifluoromethyl cyclic ethercompounds of formulae Ia and Ib may be administered via either oral,parenteral (e.g., intravenously, intramuscularly or subcutaneously) ortopical routes to mammals. These compounds may be administered alone orin combination with pharmaceutically acceptable carriers or diluents byany of the routes indicated above, and may be carried out in single ormultiple doses. The compounds prepared by the methods of the inventionmay be administered in a wide variety of different dosage forms, e.g.,combined with various pharmaceutically acceptable inert carriers in theform of tablets, capsules, lozenges, trochees, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrupsand the like.

EXAMPLES

[0092] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples.

Example 1

[0093]

[0094] Acetic acid 2-(2-acetyl-5-methoxy-phenyl)-ethyl esterThiscompound was prepared by modification of a known procedure. Sternberg,E. D.; Vollhardt, K. P. C. J. Org. Chem. 7984, 49, 1574-1583. To asolution of aluminum tribromide (43.8 g, 164 mmol) in dichloromethane(70 mL) at 0° C. was slowly added acetyl bromide (14.6 mL, 197 mmol).The reaction mixture was warmed to 15° C. and2-(3-methoxy-phenyl)-ethanol (10.0 g, 65.7 mmol) in dichloromethane(20.0 mL) was added over 45 minutes. The reaction mixture was stirredfor one hour and then poured over ice (100 mL). To the mixture was added1 N aqueous hydrochloric acid (100 mL). The organic layer was separatedand the aqueous layer was extracted with dichloromethane (100 mL). Thecombined organic extracts were washed with 1N aqueous sodium hydroxide(100 mL), dried over magnesium sulfate, filtered through Celite andconcentrated to afford acetic acid 2-(2-acetyl-5-methoxy-phenyl)-ethylester as an oil (14.8 g, 95%).¹H NMR (300 MHz, CDCl₃) δ2.05(s, 3), 2.59(s, 3), 3.29 (t, 2,J=6.9), 3.89 (s, 3), 4.33 (t, 2, J=6.9), 6.81 (d, 1,J=2.5), 8.85 (dd, 1, J=8.6, 2.6), 7.82 (d, 1, J=8.6).

[0095]¹³C NMR (75 MHz, CDCl₃) δ22.28, 30.37, 35.36, 56.63, 66.11,101.21, 112.63, 119.17, 131.00, 134.23, 142.90, 163.24, 172.32. IR 1737,1674, 1604, 1567, 1358, 1239, 1037 cm⁻¹. Analysis calculated forC₁₃H₁₆O₄: C, 66.09; H, 6.83. Found: C, 65.71; H, 7.21.

Example 2

[0096]

[0097] Acetic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethylesterTo a solution of acetic acid 2-(2-acetyl-5-methoxy-phenyl)-ethylester (12.5 g, 52.9 mmol)and cesium fluoride (0.964 g, 6.35 mmol) indimethylformamide (75 mL) at 0° C. was slowly addedtrifluoromethyltrimethylsilane (10.2 mL, 69.0 mmol). The reactionmixture was stirred 45 minutes after which GS/MS and HPLC analysisshowed no starting material. For characterization purposes, the reactionmixture was poured into water and extracted with methyl tert-butyl ether(100 mL). The organic layer was washed with water (2×75 mL) and brine(50 mL), dried over magnesium sulfate, filtered and concentrated toprovide acetic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethylester as a crude oil. ¹H NMR (300 MHz, CDCl₃) δ0.19 (s, 9), 1.93 (s, 3),2.10 (s, 3), 3.23-3.33 (m, 1), 3.42-3.52 (m, 1), 3.83 (s, 3), 4.26-4.32(m, 2), 6.77 (dd, 1, J=8.9, 2.8), 6.86 (d, 1, J=2.9), 7.32 (d, 1, J8.9).¹³C NMR (100 MHz, CDCl₃) δ2.03, 21.03, 24.64, 32.86, 55.11, 65.54, 78.90(q, J=30.3), 111.26, 117.44, 125.70 (q, J=287), 129.56, 129.79, 139.77,159.17, 171.09. IR 2961, 1741, 1610, 1383, 1286, 1255, 1165, 1140, 1039,864, 846 cm⁻¹. Analysis calculated for C₁₇H₂₅F₃O₄ Si: C, 53.95; H, 6.66.Found: C, 53.72; H, 6.53.

Example 3

[0098]

[0099] Acetic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethylesterTo the crude reaction mixture described in example 2 containing asolution of acetic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethylester was added tetrabutylammonium fluoride (52.9 mL of a 1.0 M solutionin tetrahydrofuran, 52.9 mmol). The reaction mixture was stirred onehour after which GC/MS and HPLC analysis showed no starting material.For characterization purposes, the reaction mixture was poured intowater and extracted with methyl tert-butyl ether (75 mL). The organiclayer was washed with water (75 mL) and brine (50 mL), dried overmagnesium sulfate, filtered and concentrated to provide a crude oil. ¹HNMR (400 MHz, CDCl₃) δ1.82 (s, 3), 2.01 (s, 3), 2.98-3.06 (m, 2), 3.55(dt, 1, J=13.7, 6.8), 3.79 (s, 3), 4.27-4.34 (m, 2), 6.73-6.77 (m, 2),7.28 (d, 1, J=8.5). ¹³C NMR (100 MHz, CDCl₃) δ20.92, 25.50, 34.16,55.10, 66.49, 76.67 (q, J=30.3),111.55, 118.25, 126.02 (q,J=286),128.67, 129.56, 139.70, 159.20, 171.32. IR 3453, 1720, 1610,1249, 1161, 1134, 1038 cm⁻¹. Analysis calculated for C₁₄H₁₇F₃O₄: C,54.90; H, 5.59. Found: C, 55.03; H, 5.85.

Example 4

[0100]

[0101]1,1,1-Trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-olTothe crude reaction mixture described in example 3 containing acetic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethylester was added 1N aqueous sodium hydroxide (75.0 mL, 75 mmol). Thereaction mixture was allowed to warm to room temperature and was stirred12 hours. The reaction mixture was poured into water (75 mL) andextracted with methyl tert-butyl ether (150 mL). The organic layer waswashed with water (75 mL) and brine (75 mL), dried over magnesiumsulfate, and concentrated to an oil. To the crude oil was added hexanes(20 mL) and methyl tert-butyl ether (4 mL) and a solid precipitated. Themixture was stirred for 30 minutes and filtered to provide1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol(7.3 g, 52% overall yield from acetic acid2-(2-acetyl-5-methoxy-phenyl)-ethyl ester). M.p. 110-111° C. ¹H NMR (300MHz, CDCl₃) δ1.83 (s, 3), 2.91 (dt, 1, J=13.7, 3.9), 3.76 (ddd, 1,J=13.7, 9.3, 4.4), 3.85 (s, 3), 3.85-3.93 (m, 1), 4.08 (dt, 1 ,J=9.3,3.7), 6.80-6.83 (m, 2), 7.38 (d, 1, J=8.4).

[0102]¹³C NMR (100 MHz, CDCl₃) δ26.01, 36.12, 55.19, 64.13, 76.52 (q,j=28.9), 111.47, 117.43, 125.99 (q, J=287), 129.69, 129.94, 140.86,159.55. IR 3395, 3162, 1610, 1513,1467, 1248, 1157, 1087, 1046 cm⁻¹.Analysis calculated for C₁₂H₁₅F₃O₃: C, 54.54; H, 5.72. Found: C, 54.65;H, 5.70.

Example 5

[0103]

[0104] 6-Methoxy-1-methyl-1-trifluoromethyl-isochromanTo a solution of1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol(5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added triethylamine(9.20 mL, 66.3 mmol). The solution was cooled to 0° C. andmethanesulfonyl chloride (1.61 mL, 20.8 mmol) was added dropwise. Thereaction mixture was allowed to warm to room temperature and was stirred12 hours. The formation of methanesulfonic acid2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethylester is rapid and its disappearance was monitored by HPLC (retentiontime=4.5 minutes, Zorbax Rx-C6 column 4.6×150 mm, 40° C., 50% CH₃CN/50%(0.2% Et₃N, 0.1% H₃PO₄ aqueous pH=3.2 buffer), 1 mL/min). At the end ofthe reaction, the mixture was poured into 1N aqueous hydrochloric acid(30 mL) and was extracted with dichloromethane (20 mL). The organicextracts were dried over magnesium sulfate, filtered, and concentratedto afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil(3.40 g, 73%). ¹H NMR (300 MHz, CDCl₃) δ1.69 (s, 3), 2.85-2.90 (m, 2),3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1,J=2.6), 6.85(dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). ¹³C NMR (100 MHz, CDCl₃)δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85,125.96 eq, J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611,1505, 1162, 1137, 1101 cm⁻¹. Analysis calculated for C₁₂H₁₃F₃O₂: C,58.54; H, 5.32. Found: C, 58.27; H, 5.35.

Example 6

[0105]

[0106] (2-Acetyl-5-methoxy-phenyl)-acetic acidTo a solution of aluminumtribromide (57.6 g, 216 mmol) in dichloromethane (90 mL) at 0° C. wasslowly added acetyl chloride (11.5 mL, 162 mmol). To the reactionmixture was added (3-methoxy-phenyl)-acetic acid (17.9 g, 108 mmol) indichloromethane (20.0 mL). The reaction mixture was stirred for one hourand then poured over ice (100 mL). The organic layer was separated and1N aqueous sodium hydroxide was added (100 mL). The biphasic mixture wasstirred vigorously for 90 minutes and the layers were separated. Theorganic layer was discarded and concentrated hydrochloric acid was addedto the aqueous layer until the pH reached 1. A solid precipitated andwas filtered and air-dried to afford (2-acetyl-5-methoxy-phenyl)-aceticacid (16.8 g, 75%). M.p. 153-155° C. ¹H NMR (300 MHz, CDCl₃) δ2.68 (s,3), 3.91 (s, 3), 3.92 (s, 2), 6.92-6.95 (m, 2), 7.88 (d, 1, J=9.5). ¹³CNMR (100 MHz, CDCl₃) δ28.33, 41.43, 55.46, 112.54, 118.26, 129.17,133.08, 136.94, 162.65, 174.80, 200.96. IR 3435, 1704, 1663, 1609, 1568,1258 cm⁻¹. Analysis calculated for C₁₁H₁₂O₄: C, 63.45; H, 5.81. Found:C, 63.35; H, 5.46.

Example 7

[0107]

[0108] (2-Acetyl-5-methoxy-phenyl)-acetic acid methyl esterTo a solutionof (2-acetyl-5-methoxy-phenyl)-acetic acid (5.00 g, 24.0 mmol) inmethanol (50 mL) was added concentrated sulfuric acid (1.0 mL). Thereaction mixture was stirred at room temperature for 16 hours afterwhich it was concentrated to a low volume. Dichloromethane (50 mL) wasadded and the solution was washed with 1N sodium hydroxide (50 mL). Thelayers were separated and the organic layer was dried over magnesiumsulfate, filtered, and concentrated to an oil which solidified onstanding to afford (2-acetyl-5-methoxy-phenyl)-acetic acid methyl ester(4.70 g, 88%). M.p. 74-76° C. ¹H NMR (300 MHz, CDCl₃) δ2.58 (s, 3), 3.74(s, 3), 3.89 (s, 3), 3.95 (s, 2), 6.78 (d, 1, J=2.6), 6.89 (dd, 1,J=8.7, 2.6), 7.89 (d, 1, J=8.6). ¹³C NMR (75 MHz, CDCl₃) δ29.65, 42.35,53.11, 56.69, 113.17, 120.00, 130.52, 134.39, 138.90, 163.54, 173.23,200.35. IR 1739, 1665, 1605, 1568, 1321, 1247, 1165 cm⁻¹.

[0109] Analysis calculated for C₁₂H₁₄O₄: C, 65.85; H, 6.35. Found: C,64.87; H, 6.44.

Example 8

[0110]

[0111][5-Methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-aceticacid methyl esterTo a solution of (2-acetyl-5-methoxy-phenyl)-aceticacid methyl ester (2.00 g, 9.00 mmol) and cesium fluoride (96.0 mg,0.632 mmol) in dimethylformamide (12 mL) at 0° C. was slowly addedtrifluoromethyltrimethylsilane (1.73 mL, 11.7 mmol). The reactionmixture was stirred at 0° C. for 7 hours. For characterization purposes,the reaction mixture was poured into water and extracted with methyltert-butyl ether (50 mL). The organic layer was washed with water (2×75mL) and brine (50 mL), dried over magnesium sulfate, filtered andconcentrated to provide[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-aceticacid methyl ester as an oil. ¹H NMR (400 MHz, CDCl₃) δ0.11 (s, 9), 1.89(s, 2), 3.68 (s, 3), 3.77 (s, 3), 3.98 (d, 1, J=17.2), 4.28 (d, 1,J=17.0), 6.74-6.77 (m, 2), 7.29 (d, 1, J=9.1). ¹³C NMR (100 MHz, CDCl₃)δ1.87, 24.25, 39.32, 51.75, 55.12, 78.67 (q, J=30.3), 111.97, 118.30,125.70 (q, J=286), 129.50, 129.57, 136.10, 159.17, 172.81. IR 2956,1745, 1611, 1577, 1467, 1436, 1290, 1256, 1166, 1092, 989, 863, 847cm⁻¹. Analysis calculated for C₁₆H₂₃F₃O₄Si: C, 52.73; H, 6.36. Found: C,52.84; H, 6.36.

Example 9

[0112]

[0113] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-3-oneTo the crudereaction mixture described in example 8 containing a solution of[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-aceticacid methyl ester was added tetrabutylammonium fluoride (9.00 mL of a1.0 M solution in tetrahydrofuran, 9.00 mmol). The reaction mixture wasstirred for 1 hour after which it was poured into water (50 mL) andextracted with methyl tert-butyl ether (50 mL). The organic layer waswashed with water (50 mL) and brine (30 mL), dried over magnesiumsulfate, filtered, and concentrated to afford6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one as an oil (1.26 g,54%). ¹H NMR (400 MHz, CDCl₃) δ1.89 (s, 3), 3.71 (d, 1, J=20.6), 3.79(s, 3), 3.89 (d, 20.8), 6.65 (d, 1, J=1.5), 6.85-6.89 (m, 1), 7.29 (d,1, J=8.7). ¹³C NMR (100 MHz, CDCl₃) δ21.45, 34.32, 55.33, 83.01 (q,J=30.3), 112.21, 113.88, 120.57, 124.68 (q, J=285.7), 127.73, 132.18,160.75, 167.45. IR 1765, 1614, 1509, 1322, 1301, 1274, 1259, 1183, 1101,997, 813 cm⁻¹.

[0114] Analysis calculated for C₁₂H₁₁F₃O₃: C, 55.39; H, 4.26. Found: C,55.03; H, 4.54.

Example 10

[0115]

[0116] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-3-olTo a solution6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one (1.50 g, 5.76mmol) in tetrahydrofuran (30 mL) at 0° C. was added sodium borohydride(0.240 g, 6.34 mmol) followed by boron trifluoride diethyl ether complex(0.992 g, 8.07 mmol). The reaction mixture was warmed to roomtemperature and was stirred overnight. The reaction mixture was added towater (75 mL) and extracted with methyl-tert-butyl ether (75 mL). Thelayers were separated and the organic layer was washed with 1N aqueoushydrochloric acid (50 mL), dried over magnesium sulfate, filtered, andconcentrated to afford6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol as an oil and amixture of a and b anomers (1.19 g, 79%). Data reported for the majordiastereoisomer. ¹H NMR (400 MHz, CDCl₃) δ1.74 (s, 3), 2.85 (dd, 1,J=15.7, 4.3), 2.88-2.99 (m, 1), 3.11 (dd, 1, J=15.7, 3.2), 3.80 (s, 3),5.63 (t, 1, J=3.7), 6.69 (d, 1, J=2.7), 6.82 (dd, 1, J=8.7, 2.7),7.22-7.27 (m, 1). ¹³C NMR (100 MHz, CDCl₃, data reported foridentifiable signals of the major diastereoisomer) δ24.52, 35.46, 55.16,90.71, 113.11, 113.98, 125.22, 127.57, 132.98, 159.59. IR 3439, 2949,1735, 1613, 1506, 1166, 1141, 1070 cm⁻¹

Example 11

[0117]

[0118] 6-Methoxy-1-methyl-1-trifluoromethyl-isochromanTo a solution of6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol (8.36 g, 31.9 mmol)in dichloromethane (84 mL) was added triethylsilane (15.3 mL, 95.8 mmol)followed by trifluoroacetic acid (14.7 mL, 191 mmol). The reaction wasstirred at room temperature for 2 hours and was poured into 1N aqueoussodium hydroxide (250 mL). The organic layer was separated and washedwith 1N aqueous sodium hydroxide (100 mL). The organic layer was driedover magnesium sulfate, filtered, and concentrated to afford6-methoxy-1-methyl-1-trifluoromethyl-isochromanas an oil (6.88 g, 88%).¹H NMR (300 MHz, CDCl₃) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3),3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1,J=8.7, 2.6), 7.31 (d, 1, J=8.7). ¹³C NMR (100 MHz, CDCl₃ ) δ23.25,29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96(q, J=289), 127.86,136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505,1162, 1137, 1101 cm⁻¹. Analysis calculated for C₁₂H₁₃F₃O₂: C, 58.54; H,5.32. Found: C, 58.27; H, 5.35.

Example 12

[0119]

[0120] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehydeTohexamethylenetetramine (31.3 g, 223 mmol) was added trifluoroacetic acid(400 mL) and the mixture was heated to 70° C. for 90 minutes. A solutionof 6-methoxy-1-methyl-1-trifluoromethyl-isochroman (50.0 g, 203 mmol) intrifluoroacetic acid (100 mL) was then added to the reaction mixtureover 40 minutes. The solution was stirred for 3 hours and water wasadded (450 mL). The reaction mixture was stirred 16 hours, cooled toroom temperature, and poured into methyl tert-butyl ether (500 mL). Theorganic layer was separated and washed with water (3×300 mL). Theorganic layer was poured into a round bottom flask and cooled to 0° C.6N Sodium hydroxide was added in portions until the pH raised to 10(˜500 mL). The organic layer was separated, washed with water (200 mL),dried over magnesium sulfate, filtered, and concentrated to afford6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde as an oil(54.2 g of a 12:1 mixture of regioisomers, 97%). ¹H NMR (400 MHz, CDCl₃)δ1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1), 3.97 (s, 3),4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1). ¹³C NMR (75MHz, CDCl₃) δ23.07, 29.98, 55.73, 60.83, 76.03 (q, J=27.4), 111.81,112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06, 160.89, 188.92. IR1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm⁻¹. Analysiscalculated for C₁₃H₁₃F₃O₃: C, 57.13; H, 5.05. Found: C, 56.94; H, 4.78.

Example 13

[0121]

[0122]N′-1-[(E)-1-(6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-isochromen-7-yl)methylidene]-4-methyl-1-benzenesulfonohydrazideToa solution of the crude6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde (54.2 g,198 mmol) obtained from example 12 in methanol (542 mL) was addedp-toluenesulfonhydrazide (36.9 g, 198 mmol) followed by 2% aqueousacetic acid (81.3 mL). The reaction mixture was heated to reflux for 90minutes and cooled to room temperature. A solid precipitated and wasfiltered to provideN′-1-[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochromen-7-yl)methylidene]-4-methyl-1-benzenesulfonohydrazide(45.46 g, 52%). M.p.=181-183° C. ¹H NMR (300 MHz, CDCl₃) δ1.71 (d, 3,J=0.7), 2.44 (s, 3), 2.85-2.89 (m, 2), 3.84 (s, 3), 3.93 (dt, 1, J=11.2,5.6), 4.16 (dt, 1, J=11.2, 5.6), 6.65 (s, 1), 7.33 (d, 2, J=8.1), 7.79(d, 1, J=1.2), 7.89 (d, 2, J=8.4), 8.13 (s, 1). ¹³C NMR (75 MHz, CDCl₃)δ21.48, 23.07, 29.50, 55.47, 60.99, 76.02 (q, J=27.4), 110.91, 120.45,124.74, 125.04, 125.72 (q, J=287), 127.95, 129.45, 134.97, 138.97,143.34, 144.22, 157.04. IR 3223, 1623, 1505, 1417, 1325, 1289, 1275,1172, 1157, 1123, 1098, 918, 658 cm⁻¹. Analysis calculated forC₂₀H₂₁F₃N₂O₄S: C, 54.29; H, 4.78; N, 6.33. Found. C, 54.34; H, 4.73; N,6.37.

Example 14

[0123]

[0124] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehydeAmixture of copper(II)chloride (52.7 g, 309 mmol) andN′^(˜)1^(˜)[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochromen-7-yl)methylidene]-4-methyl-1-benzenesulfonohydrazide(45.5 g, 103 mmol) in tert -butyl alcohol (910 mL) and water (228 mL)was heated to 70° C. for 2.5 hours. The reaction mixture was cooled toroom temperature, concentrated to about 300 mL and poured into methyltert-butyl ether (500 mL) and water (500 mL). The mixture was stirred 15minutes and filtered. The filtrate was poured into methyl tert-butylether (200 mL) and the layers were separated. The organic layer waswashed with water (4×250 mL), dried over magnesium sulfate, filtered,and concentrated to provide6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde as an oilwhich solidified on standing (26.8 g, 95%). M.p.=82-93° C. ¹H NMR (400MHz, CDCl₈) 1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1),3.97 (s, 3), 4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1).¹³C NMR (75 MHz, CDCl₃) δ23.07, 29.98, 55.73, 60.83, 76.03 (q, J=27.4),111.81, 112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06, 160.89,188.92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874cm⁻¹.

[0125] Analysis calculated for C₁₃H₁₃F₃O₃: C, 57.13; H, 5.05. Found: C,56.94; H, 4.78.

Example 15

[0126]

[0127](2S,3S)-[(1R)-6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl]-(2-phenyl-piperidin-3-yl)-amine(S)-(+)-mandelateSodium triacetoxyborohydride (11.61 g, 54.8 mmol) wasadded in one portion to water bath chilled slurry of6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde (7.51 g,27.4 mmol) and (2S-3S)-2-phenyl-piperidin-3-ylamine dimandelate (13.8 g,28.7 mmol) in dichloromethane (150 mL). Within 15 minutes most startingmaterial was dissolved and slow precipitation of product began shortlyafter. The reaction mixture was stirred 2.5 hour at room temperature,cooled to 0° C., and 1N aqueous sodium hydroxide (150 mL) was addedslowly. The layers were separated, the aqueous layer (pH 9) wasextracted with dichloromethane (50 mL). The combined organic extractswere stirred one hour with 1N aqueous sodium hydroxide (100 mL), thelayers were separated and the organic layer was washed with water (50mL), brine (50 mL), dried over Na₂SO₄, and filtered. The solvent wasevaporated and the resulting off-white foam vacuum dried to give 11.08 g( 93% ) of the crude product. S-(+)Mandelic acid (7.55 g, 49.6 mmol )dissolved in ethanol (100 mL) was added to a solution of the mixture ofdiastereomers of(6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine(10.78 g, 24.8 mmol) in ethanol (300 mL) at room temperature. Themixture was stirred and crystallization began to proceed. After stirringovernight, the mixture was filtered to yield 4.66 g (32% ) of(6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine(S)-(+)-mandelate as a mixture of diastereomers (81:19 ratio by HPLCanalysis). ¹H NMR (400 MHz, CDCl₃ data reported for majordiastereoisomer) δ1.42-1.64 (m, 2), 1.53 (s, 3), 1.72-1.79 (m, 1),1.94-1.98 (m, 1), 2.46-2.89 (m, 4), 3.15-3.28 (m, 3), 3.45 (s, 3),3.47-3.78 (m, 1), 3.92-3.97 (m, 2), 4.27 (bs, 1), 4.52 (s, 1), 6.66 (s,1), 7.04-7.19 (m, 4), 7.27-7.36 (m, 7). ¹³C NMR (100 MHz, CDCl₃) δ16.99,22.53, 25.96, 28.58, 45.05, 45.46, 53.52, 53.95, 55.08, 60.61, 61.86,73.25, 75.54 (q, J=28.2), 110.36, 126.02, 126.27, 126.32, 126.42,126.55, 127.01, 127.43, 127.57, 128.27, 135.04, 137.83, 143.16, 156.51,174.59. IR 3441, 1576, 1358, 1160, 1136, 1098, 1038, 775, 756, 698 cm⁻¹.Analysis calculated for C₃₂H₃₇F₃N₂O₅: C, 65.52; H, 6.36; N, 4.78. Found:C, 65.55; H, 6.03; N, 4.84.

Example 16

[0128]

[0129](2S,3S)[(1R)-6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl]-(2-phenyl-piperidin-3-yl)-aminedihydrochloride(6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine(S)-(+)-mandelate (2.25 g of a 81:19 mixture of diastereoisomer, 3.84mmol) was stirred overnight in diisopropyl ether (23 mL) and 1N aqueoussodium hydroxide (23 mL). The layers were separated and the organiclayer washed with water (20 mL) and brine (20 mL). The organic layer wasconcentrated to a crude waxy solid and methanol (15 mL) was added. Thesolution was stirred at room temperature and a solution of 1.5N aqueoushydrochloric acid (5.0 mL) was added dropwise. The dihydrochloride saltprecipitated immediately and the white slurry was stirred overnight atroom temperature, filtered and dried under vacuum to afford(6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-aminedihydrochloride (1.282 g, 66%) as a 96:4 mixture of diastereoisomers.The diastereomeric ratio could be further increase by crystallizationfrom methanol/water (75/25). ¹H NMR (400 MHz, D₂O, data reported formajor diastereoisomer) δ1.52 (s, 3), 1.80-1.92 (m, 2), 1.95-2.50 (m, 1),2.21-2.26 (m, 1), 2.63-2.71 (m, 2), 3.04-3.11 (m, 1), 3.36 (s, 3),3.45-3.49 (m, 1), 3.65-3.81 (m, 3), 3.90-3.96 (m, 1), 4.09 (d, 1,J=13.5), 6.46 (s, 1), 6.98-7.07 (m, 3), 7.23-7.25 (m, 2), 7.30 (t, 1,J=7.5). IR 2958, 1457, 1377, 1143, 749, 692 cm⁻¹. Analysis calculatedfor C₂₄H₃₁Cl₂F₃N₂O₂: C, 56.81; H, 6.16; Cl, 13.97; N, 5.52. Found: C,56.69; H, 6.31; Cl, 14.13; N, 5.55.

1. A process for preparing a mixture of compounds of formulae Ia and Ib:

enriched in the compound of formula Ia, and pharmaceutically acceptablesalts thereof, wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆alkyl or phenyl or substituted phenyl; R³ is hydrogen or halo; m iszero, one or two; comprising the steps of (a1) reacting a mixture ofcompounds of formulae Ia and Ib:

with an acid of formula HX, wherein HX is selected from the groupconsisting of (S)-(+)-mandelic acid, D-(−)-tartaric acid,di-p-toluoyl-D-tartaric acid,((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, aceticacid and hydrobromic acid, to form a mixture of diastereomeric compoundsof formulae Va and Vb, respectively:

(b1) permitting the HX salt of the diastereomeric product mixture ofstep (a1) to crystallize out of a solution thereof in an appropriatesolvent; (c1) treating the resulting mixture of compounds obtained fromstep (b1) with a base to obtain a mixture of compounds Ia and Ib, thatis enriched in the compound of formula Ia; said process furthercomprising the step of reacting a compound of formula III:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; m is zero, one or two; with a compound of formulaIV:

wherein R³ is hydrogen or halo; in the presence of a reducing agent toform a mixture of diastereomeric compounds of formula Ia and Ib:
 2. Aprocess according to claim 1 wherein the reducing agent is selected fromthe group consisting of sodium triacetoxyborohydride, sodiumcyanoborohydride and sodium borohydride.
 3. A process according to claim1 wherein the reducing agent is sodium triacetoxyborohydride.
 4. Amixture of compounds of formulae Ia and Ib:

or pharmaceutically acceptable salts thereof, wherein R¹ is C₁-C₆ alkyl;R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenyl or substituted phenyl; R³is hydrogen or halo; m is zero, one or two; and ratio of the compound offormula Ia to Ib is 90:10 or greater.
 5. A mixture according to claim 4wherein the ratio is 98:2 or greater.
 6. A mixture of compounds of theformulae Va and Vb:

highly enriched in the compound of formula Va, wherein R¹ is C₁-C₆alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenyl or substitutedphenyl; R³ is hydrogen or halo; m is zero, one or two; wherein HX isselected from the group consisting of (S)-(+)-mandeli acid,D-(−)-tartaric acid, di-p-toluoyl-D-tartaric acid,((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, aceticacid and hydrobromic acid.
 7. A mixture according to claim 6 wherein HXis (S)-(+)-mandelic acid.
 8. A process according to claim 1 furthercomprising the step of formulating a compound of formula II:

wherein R¹ is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenyl or substitutedphenyl; R³ is hydrogen or halo; m is zero, one or two; via the reactionwith hexamethylenetetramine in the presence of an acid to form acompound of formula III:


9. A process according to claim 8 wherein the acid is selected from thegroup consisting of trifluoroacetic acid, glyceroboric acid, acetic acidand hydrochloric acid.
 10. A process according to claim 8 wherein theacid is trifluoroacetic acid.
 11. A process according to claim 1 whereinthe compound of formula II:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; R³ is hydrogen or halo; m is 0, 1 or 2; isprepared by a process comprising the steps of: (a2) reacting a compoundof formula VII:

with a compound of formula CF₃SiR⁴ ₃, wherein R⁴ is (C₁-C₆)alkyl orphenyl, in the presence of a fluoride source to form a compound offormula VIII:

(b2) removing the silyl protecting group from the product of step (a2)via treatment with a base or a fluoride source to form a compound offormula IX:

(c2) hydrolysis of the ester group of the product of step (b2) in thepresence of a base to fo a compound of formula X:

and (d2) performing a ring cyclization reaction on the product of step(c2) in the presence base and an activating agent selected from thegroup consisting of methanesulfonyl chlori methanesulfonic anhydride,p-toluenesulfonyl chloride, p-toluenesulfonic anhydride and triflicanhydride.
 12. A process according to claim 11 wherein the fluoridesource in step (a2) is selected from the group consisting of cesiumfluoride, potassium fluoride and an alkylammonium fluoride.
 13. Aprocess according to claim 11 wherein the alkylammonium fluoride istetrabutylammonium fluoride.
 14. A process according to claim 11 whereinthe fluoride source in step (a2) is cesium fluoride.
 15. A processaccording to claim 11 wherein the base in step (b2) is sodium hydroxideor potassium hydroxide.
 16. A process according to claim 11 wherein thepreferred fluoride source of step (b2) is tetrabutylammonium fluoride,cesium fluoride, hydrofluoric acid-pyridine complex or hydrofluoricacid.
 17. A process according to claim 11 wherein the fluoride source instep (b2) is tetrabutylammonium fluoride.
 18. A process according toclaim 11 wherein the base in step (c2) is selected from the groupconsisting of sodium hydroxide, potassium hydroxide, sodium carbonate,sodium bicarbonate, potassium carbonate, and potassium bicarbonate. 19.A process according to claim 11 wherein the base in step (c2) is sodiumhydroxide.
 20. A process according to claim 11 wherein the activatingagent in step (d2) is methanesulfonyl chloride.
 21. A process accordingto claim 11 wherein the base for step (d2) is selected from the groupconsisting of triethylamine, diisopropylethylamine, 2,6-lutidine,pyridine, sodium hydroxide, potassium hydroxide, cesium carbonate andpotassium carbonate.
 22. A process according to claim 11 wherein thebase for step (d2) is triethylamine.
 23. A process according to claim 1wherein the compound of formula II:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; R³ is hydrogen or halo; m is 0, 1 or 2; isprepared by a method comprising the steps of: (a3) reacting a compoundof formula XI:

with an alcohol of formula R¹OH in the presence of an acid, wherein R¹is as defined abo to form a compound of formula XII:

(b3) reacting the product of step (a3) with compound of formula CF₃SiR⁴₃, wherein R⁴ (C₁-C₆)alkyl or phenyl, to form a compound of formulaXIII:

(c3) reacting the product of step (b3) with a fluoride source to obtaina lactone compound formula XIV:

(d3) reacting the lactone product of step (c3) with a reducing agentoptionally in the presen of a Lewis acid to obtain a compound of formulaXV:

and (e3) reacting the product of step (d3) with a reducing agent in thepresence of a Lewis acid.
 24. A process according to claim 23 whereinthe acid of step (a3) is chosen from the group consisting of sulfuricacid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid andmethanesulfonic acid.
 25. A process according to claim 23 wherein theacid of step (3) is sulfuric acid.
 26. A process according to claim 23wherein the fluoride source of step (b3) is selected from the groupconsisting of cesium fluoride, potassium fluoride, and an alkylammoniumfluoride.
 27. A process according to claim 26 wherein the alkylammoniumfluoride is tetrabutylammonium fluoride.
 28. A process according toclaim 23 wherein the fluoride source of step (b3) is cesium fluoride.29. A process according to claim 23 wherein the fluoride source for step(c3) is selected from the group consisting of tetrabutylammoniumfluoride, cesium fluoride, hydrofluoric acid-pyridine complex, andhydrofluoric acid.
 30. A process according to claim 23 wherein thefluoride source for step (c3) is tetrabutylammonium fluoride.
 31. Aprocess according to claim 23 wherein the reducing agent for step (d3)is selected from the group consisting of sodium borohydride, boranetetrahydrofuran complex, borane dimethylsulfide complex, diborane,lithium borohydride, calcium borohydride, lithium aluminum hydride,diisobutylaluminum hydride, L-selectride and K-selectride.
 32. A processaccording to claim 23 wherein the Lewis acid for step (d3) is borontrifluoride diethyl ether complex.
 33. A process according to claim 23wherein the reducing agent for step (e3) is triethylsilane ortriphenylsilane.
 34. A process according to claim 23 wherein the Lewisacid for step (e3) is boron trifluoride etherate or trifluoroaceticacid.
 35. A process according to claim 23 wherein the reducing agent forstep (e3) is selected from the group consisting of platinum, platinumoxide, and palladium hydroxide in the presence of hydrogen gas.
 36. Aprocess according to claim 1 further comprising the step of purifying acompound of formula III:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; and m is zero, one or two, comprising the stepsof (a4) forming a hydrazone via the reaction of a compound of formulaIII with a hydrazone of formula XVI:

wherein R¹ is as defined above, in the presence of an acid to afford acompound of formu XVII:

and (b4) hydrolyzing the product of step (a4) via treatment with areagent selected from th group consisting of copper(II)chloride,copper(II)iodide, copper(II)acetate, copper sulfate, sulfuric acid,acetic acid and hydrochloric acid.
 37. A process according to claim 36wherein the acid in step (a4) is selected from the group consisting ofacetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid andp-toluenesulfonic acid.
 38. A process according to claim 36 wherein theacid in step (a4) is acetic acid.
 39. A process according to claim 36wherein the reagent for step (b4) is copper(II)chloride.
 40. A compoundof formula VIII:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; R⁴ is (C₁-C₆)alkyl or phenyl; and m is zero, oneor two.
 41. A compound of formula IX:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; and m is zero, one or two.
 42. A compound offormula XIII:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; R⁴ is (C₁-C₆)alkyl or phenyl; and m is zero, oneor two.
 43. A compound of formula XIV:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; and m is zero, one or two.
 44. A compound offormula XV:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; and m is zero, one or two.
 45. A compound offormula XVII:

wherein R¹ is C₁-C₆ alkyl; R² is C₁-C₆ alkyl, halo C₁-C₆ alkyl or phenylor substituted phenyl; and m is zero, one or two.